The goal of these studies is to determine the efficacy of proprietary geranylgeranyl diphosphate synthase inhibitors (GGSIs), for inhibition of osteoclast mediated bone resorption in comparison to current standard-of-care agents. We have developed a group of proprietary bisphosphonates containing isoprene substructures that demonstrate highly potent and specific GGSI activity in vitro. These compounds do not contain the hydroxyl group or the nitrogen substructure of the current bisphosphonates, which are used clinically. Our GGSIs represent a significant advance in bisphosphonate development in that they target a downstream enzyme relative to the clinical bisphosphonates. We feel that further development of our novel GGSIs for the treatment of osteoporosis is warranted based on the strength of our preliminary studies and the ongoing need for additional treatments for this disease which represents a significant and growing public health problem. Indeed, it is estimated that by 2025 osteoporosis will result in $25 billion worth of health costs each year. Here we propose SBIR Phase I studies to prove the feasibility of GGSIs in osteoporosis in a commonly used rat model of the disease. The feasibility studies described in this proposal provide a streamlined approach towards identification of the most active GGSI towards bone resorption from our library using in vitro models, and transition of these active compounds into an in vivo model of bone resorption. In specific aim one we will use cell based models to prioritize our compounds based on osteoclast resorption activity and inhibition of osteoblast apoptosis. Then in specific aim two we will use the highest priority compound in an ovariectomized rat model of osteoporosis and correlate the in vitro data to in vivo measurements of bone strength, biomarkers of mechanism engagement, biomarkers of bone resorption, and ex vivo markers of osteoblast apoptosis. Together these aims will provide us with a go or no-go decision for more elaborate IND enabling studies.